This project is designed to test the hypothesis that (1) gastrointestinal (g.i.) Tolerance to an dependence upon opioid drugs result primarily from drug actions mediated by mu opioid receptors in the brain and (2) drug actions at mu, delta and kappa opioid receptors in the g.i. track contribute to the dependence/withdrawal profile in the brain. The hypothesis is based upon preliminary results, contemporary understanding of bi-directional brain-gut interactions, and modern concepts of opioid tolerance and dependence. Our preliminary data show that dependence can be demonstrated in the g.i. track of unanesthetized rats after infusion of morphine and that the dependence originates in the brain, not in the g.i. track. The proposed experiments will extend the results to include detailed examination of individual and summated opioid effects on multiple endpoints after central and peripheral administration. Specifically, we will test the hypothesis by continuous evaluation of tolerance to g.i. motility effects on receptor-selective opioids during infusion into the brain or periphery in unanesthetized rats, followed by administration of receptor-selective antagonists into the brain and/or periphery. We will also assess g.i. propulsion, antinociception, and behavior relevant to acute opioid effects, tolerance, and withdrawal. These studies will provide a new pharmacological construct of opioid tolerance/dependence that links subject factors, drug factors, control factors, and functional factors.